Research Paper Volume 13, Issue 1 pp 646—674
MITF functions as a tumor suppressor in non-small cell lung cancer beyond the canonically oncogenic role
- 1 Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
- 2 Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- 3 Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
- 4 Inservice Master Program in Life Sciences, College of Life Sciences, National Chung-Hsing University, Taichung, Taiwan
- 5 Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- 6 Institute of Chemistry, Academia Sinica, Taipei, Taiwan
- 7 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
- 8 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- 9 Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan
- 10 Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
- 11 Centers for Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan
Received: June 30, 2020 Accepted: September 9, 2020 Published: December 3, 2020
https://doi.org/10.18632/aging.202171How to Cite
Copyright: © 2020 Hsiao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Microphthalamia-associated transcription factor (MITF) is a critical mediator in melanocyte differentiation and exerts oncogenic functions in melanoma progression. However, the role of MITF in non-small cell lung cancer (NSCLC) is still unknown. We found that MITF is dominantly expressed in the low-invasive CL1-0 lung adenocarcinoma cells and paired adjacent normal lung tissues. MITF expression is significantly associated with better overall survival and disease-free survival in NSCLC and serves as an independent prognostic marker. Silencing MITF promotes tumor cell migration, invasion and colony formation in lung adenocarcinoma cells. In xenograft mouse model, MITF knockdown enhances metastasis and tumorigenesis, but decreases angiogenesis in the Matrigel plug assay. Whole transcriptome profiling of the landscape of MITF regulation in lung adenocarcinoma indicates that MITF is involved in cell development, cell cycle, inflammation and WNT signaling pathways. Chromatin immunoprecipitation assays revealed that MITF targets the promoters of FZD7, PTGR1 and ANXA1. Moreover, silencing FZD7 reduces the invasiveness that is promoted by silencing MITF. Strikingly, MITF has significantly inverse correlations with the expression of its downstream genes in lung adenocarcinoma. In summary, we demonstrate the suppressive role of MITF in lung cancer progression, which is opposite to the canonical oncogenic function of MITF in melanoma.